In the United States, 30%-40% of the approximately 800,000 HIV-1 infected individuals are coinfected with hepatitis C virus (HCV). The normal course of HCV infection from chronic inflammation to cirrhosis and liver cancer progresses significantly faster in HIV-1-infected persons than in persons infected with HCV alone. The mechanism(s) for the accelerated progression of HCV-induced hepatic disease in the setting of HIV-1 coinfection is unknown. The proposed study will test the hypothesis that HIV-1 Tat exacerbates the effects of HIV induced immunosuppression by interfering with the interferon response thereby increasing the rate of HCV replication and pathogenesis. The first Specific Aim of this application is to confirm and extend studies indicating that HIV-1 Tat increases HCV RNA replication and protein expression. The antiviral proteins of the interferon family are the first line of defense against many viral infections, including HCV, and certain HCV proteins may function as interferon antagonists. Tat has been reported to modulate the expression and activity of several proteins in the interferon response pathway. The second Specific Aim is to determine effects of HIV-1 Tat on interferon-regulated effectors in hepatic cells producing HCV RNA and protein and in nonexpressing hepatic cells. The proposed studies may provide the first evidence that HIV-1 Tat increases HCV replication and pathogenesis, and suggest therapeutic strategies that can benefit the increasing patient population coinfected with these important viral pathogens. [unreadable] [unreadable] [unreadable]